Tri-substituted imidazoles

ABSTRACT

This relates to a new class of imidazoles which are substituted at the 2-carbon by an aryl or heterocyclic moiety and which are substituted at the 4 and 5 carbons by cyano, carboxy, alkoxycarbonyl, carbamoyl or N-substituted carbamoyl. These products have utility as anti-hyperuricemic agents in the treatment of gout.

United States Patent [191 Baldwin et al.

[ Oct. 21, 1975 1 Till-SUBSTITUTED IMIDAZOLES [75] Inventors: John J.Baldwin, Lansdale;

Frederick C. Novello, Berwyn, both of Pa.

[73] Assignee: Merck & Company,, Rahway, NJ.

[22] Filed: July 30, 1973 [21] Appl. No.: 383,852

-[44] Published under the Trial Voluntary Protest Program on January 28,1975 as document no. B 383,852.

Related U.S. Application Data [62] Division of Ser. No. 250,505, May 5,1972, Pat. No.

3,244,715 4/1966 Castle 260/250 AC 9/1972 Baldwin 260/294.9 5/1974Baldwin et al. 260/294.9

OTHER PUBLICATIONS Hinkel et al., J. Chem. Soc. 1937, pp. 1432 to 1437.

Malm et al., J. Heterocyclic Chemistry, Vol. 1, pp. 182 to 185, (1964).

Primary Examiner-John D. Randolph Attorney, Agent, or Firm-Daniel T.Szura; J. Jerome Behan [57] ABSTRACT This relates to a new class ofimidazoles which are substituted at the 2-carbon by an aryl orheterocyclic moiety and which are substituted at the 4 and 5 car bons bycyano, carboxy, alkoxycarbonyl, carbamoyl or N-substituted carbamoyl.These products have utility as anti-hyperuricemic agents in thetreatment of gout.

5 Claims, N0 Drawings chalky deposits in the cartilages of the joints.These de- TRl-SUBSTITUTED IMIDAZOLES This is a division of applicationSer. No. 250,505 filed May 5, 1972, now U.S. Pat. No. 3,812,136 grantedMay 21, 1974.

The invention relates to a new class of imidazoles which have utility asanti-hyperuricemic agents in the treatment of gout. These productsinhibit the action of xanthine oxidase in the body and thus effectivelyreduce the concentration of uric acid in serum and urine.

Gout is a condition affecting humans and lower animals which ischaracterized by perversion of the purine metabolism resulting in anexcess of uric acid in the blood, attacks of acute arthritis andformation of posits are made up chiefly of urates, or uric acid.

Uric acid serves biochemical function in the body and is merely an endproduct of purine metabolism. It is well known in the art that thepurine bases adenine and guanine, which play key roles in a wide varietyof chemical processes, both give rise to uric acid in the body. Adenylicacid and guanylic acid are converted to the free purine bases bydestructive metabolic enzymes. A portion of the free purine bases isconverted to purine ribonucleotides and the remainder is degraded to thefree bases xanthine and hypoxanthine. A single enzyme, xanthine oxidase,converts both xanthine and hypoxanthine to uric acid for excretion.

Although human purine biosynthesis can be inhibited at the stage offormyl glycinimide ribotide by the glutamine antagonists azaserine and6-diazo-5-oxo-lnorleucine, a high incidence of undesirable side effectsprecludes their being used clinically for this purpose. In recent years,substantial progress has been made in attempting to control theexcessive levels of uric acid in patients afflicted with gout throughthe use of pharmaceutical agents. Uric acid synthesis has beeneffectively blocked by the use of allopurinol, i.e., 4-hydroxypyrazolo-[3,4-d]-pyrimidine, a compound which is a structuralisomer of hypoxanthine. Allopurinol acts as a specific inhibitor of theenzyme xanthine oxidase, which is responsible for the conversion of bothhypoxanthine and xanthine to uric acid. As a direct result of theadministration of this compound to patients afflicted with gout, part ofthe uric acid which would normally end up in the urine is replaced bythe oxypurines, hypoxanthine and xanthine, thus greatly reducing thecontent of uric acid in serum and urine. Azathioprine has also been usedto inhibit excessive purine syn-. thesis, and thus reduce the abnormallyhigh amounts of uric acid found in the serum and urine of afflictedpatients. Other compounds, such as acetylsalicylic acid,thiophenylpyrazolidine and phenylbutazone have also been employed in thetreatment of gout. Many of the existing compounds used in the treatmentof gout, however, relieve the inflammation and other symptoms connectedtherewith but have no effect on the conditions which give rise to goutyarthritis or hyperuricemia. Thus, there is still a need for compoundswhich can be employed in the prophylactic treatment of gout as well asfor the treatment of other abnonnal conditions associated withhyperuricemia.

ONO

An object of this invention is to describe a novel class oftri-substituted imidazoles which are effective antigout andanti-hyperuricemic agents and methods of preparing same. The products ofthis invention are compounds of the following formula: i

wherein R is naphthyl such as l-or 2-naphthyl, pyridyl such as 2-, 3- or4-pyridyl or mono-substituted mononuclear aryl of the formula:

wherein X is halo, for example, chloro, bromo, fluoro or iodo and thelike, lower alkoxy, for example, methoxy, ethoxy, propoxy and the likeor lower alkanamido, for example, formamido, acetamido or propionamidoand the like; and R and R are the same or different and represent cyano,carboxy, lower alkoxycarbonyl, for example, methoxycarbonyl,ethoxycarbonyl or propoxycarbonyl and the like, carbamoyl or N- loweralkylcarbamoyl such as N-methyl-, N-ethyl-, N- propyl orN-butylcarbamoyl; and the non-toxic, pharmacologically acceptable acidaddition and quaternary ammonium salts thereof.

A preferred embodiment of this invention comprises those2-(4-pyridyl)imidazoles of formula ll, infra, wherein the 4 and 5positions of the imidazole nucleus are both substituted by carboxy orcyano or, in the alternative, by carbamoyl and cyano:

wherein the R moieties both represent carboxy or cyano at the same timeor, taken separately, one of the R radicals is cyano and the remaining Ris carbamoyl; including the non-toxic alkali metal and alkaline earthmetal and quarternary ammonium salts thereof. Typical of the productsembraced by this preferred subgroup are, for example,2-(4-pyridyl)-imidazole-4,5- dicarboxylic acid,4,5-dicyano-2-(4-pyridyl)-imidazole and 4( 5 )-cyano-2-( 4-pyridyl )-5 4imidazolecarboxamide. This class of products exhibits particularly goodantihyperuricemic activity and represents a preferred subgroup ofproducts within the scope of this invention.

The 4,5-dicarboxyimidazoles of this invention are prepared by treatingtartaric acid dinitrate with either an aralkaldehyde or with apyridinecarboxaldehyde, in the presence of ammonium hydroxide, followedby treatment with an acid such as a mineral acid:

wherein R is as defined above. In practice, it is desirable to conductthe process in the cold as, for example, at temperatures in the range offrom about lC. to +C., but following the addition of the aldehyde themixture can be allowed to warm to room temperature.

aooc n R ooc ll 1 $140M. 4 1| 1100c \q R R4OOC )R wherein R OH is alower alkanol such as methanol, ethanol or propanol, etc., R is loweralkyl and R is as defined above.

The mono-ester analog (lc, infra) of the dicarboxyl- 3O ate describedabove as formula lb, is obtained by simply treating the latter (lb) withan equivalent amount of a base as, for example, with an alkali metalhydroxide followed by treatment with a mineral acid:

R OOC 1': 3 0C I Base 11+ R 00 R HOOC wherein R and R are as definedabove.

The carboxamides of this invention, corresponding to wherein R and R areas defined above.

Likewise, the 4,5-dicarbamoylimidazoles (le, infra) are obtained fromtheir corresponding dicarboxylate precursors (lb) by treatment withammonia in a suit- 5 able solvent, preferably, methanol:

Ib I Ie wherein R and R are as defined above. And the N- Loweralkylcarbamoylimidaz oles are obtained in a manner similar to thatdescribed above for the preparation of the carbamoyl derivatives (le)except that the appropriate lower alkylamine is substituted for ammoniain an otherwise similar process.

The 4(5)-cyano-5(4)-carbamoylimidazoles and 4,5-

dicyanoimidazoles (If, infra) are derived from their4,5-dicarbamoylimidazole precursors (le) by treating the latter withphosphorus oxychloride, followed by treatment with a base such asammonium hydroxide to neutralize any'excess acid. This method can beused to prepare either the monocyano or dicyano imidazole derivativesdepending upon the reaction time employed.

The following equation, wherein phosphorus oxychloride reacts with4,5-dicarbamoylimidazole (Ie), illustrates this method of preparation;however, it is to be formula 1, supra, wherein either or both of R d Runderstood that when a shorter reaction time is emrepresent carbamoyl orN-lower alkylcarbamoyl, are derived from the corresponding esterprecursors. Thus,

I ll Nll Oll n+ nooc- N R nooc N l v H ployed the corresponding 4( 5)-cyano-5(4 )-carbamoyl- 2-imidazole is obtained:

Ie I II wherein R is as defined above.

Included within this invention are the non-toxic, pharmacologicallyacceptable salts of the instant products (1) including the quaternaryammonium and acid addition salts. In practice, the quaternary salts areobtained by treating a 2-pyridylimidazole product of this invention(formula I, supra, wherein R is pyridyl) with a lower alkyl halide suchas methyl iodide, ethyl iodide or propyl iodide in a suitable solventsuch as methanol, ethanol or dimethylformamide.

The acid addition salts include both metal salts such as the alkalimetal and alkaline earth metal salts and salts of mineral acids as, forexample, the hydrochloride and hydrobromide salts. The hydrogen atom atposition l of the imidazole ring (I) is acidic in character and reactsreadily with various bases such as the alkali metal and alkaline earthmetal hydroxides and carbonate as, for example, sodium and potassiumhydroxide, sodium carbonate, potassium carbonate and calcium carbonateto afford the corresponding salts. Likewise,

' the nitrogen atom in the 2-pyridylimidazoles of this in vention will,upon treatment with an acid such as hydrochloric acid or hydrobromicacid, afford the corresporiding hydrochloride or hydrobromide.

The foregoing and other equivalent methods for the preparation of thesalts of the instant products (I) will be apparent to those havingordinary skill in the art and, to the extent that the said derivativesare both non-toxic and physiologically acceptable to the body system,the said salts are the functional equivalents of the free imidazoleproduct (I).

The examples which follow illustrate the imidazole products (I) of thisinvention and the method by which they are prepared. However, theexamples are illustrative only and it will be apparentto those havingord1- 6 EXAMPLE 1 dropwise at 5 to l 0C. An additional 50 ml. ofconcentrated ammonium hydroxide is then added followed by the dropwiseaddition of 4-pyridinecarboxaldehyde g., 0.37 mole). The reactionmixture is cooled in ice and allowed to warm to 27C. over 16 hours. Theresulting solid is filtered dissolved with water and acidified withhydrochloric acid to yield 30 g. of 2-(4-pyridyl)imidazoIe4,5dicarboxylic acid which decomposes at 308C.

Analysis for C H N O Cale; C, 5l.5l; H, 3.03; N, 18.02 Found: C, 5l.l8;H; 3.21; N, 17.70

By substituting the appropriate carboxaldehyde for the4-pyridinecarboxaldehyde of Example 1 and following the proceduredescribed therein the products of Table l, infra, may be obtained. Thefollowing equation and table illustrate the process of Example 1 and theproducts obtained thereby:

on F 110 s 'u ll .O /l. 0

Nll Otl RCllG 3 ucll,

uooc n 4 H00 i /ILR 5 TABLE I 0 Analysis 6 R cart-5.11231- ("m-ulna- 7 2@211 274 c 50.53 58.50 a 4 .09 3 .89 11 11.38 11.35

s 3 -c(cu 3 262. 5-263.5 c 50. 1 51.11 a 5.70 5.77 N 13.20 13.48

9 4 -cu(cu 2 263 c 48.48 48. 71 u 5.09 5.12 N 14.14 14.34 10 5 Gel262-264 c 49. 49.41 a 2.65 2. o u 10. 51 10. 74 n 11 6 --zzu-cca 272 c52, 53.64 a s3 3 a1 7 8 TABLE IContinued i ze.

x R CETfiJatcciFI-ound'i 12 7 267-269 c 63.83 64.08 V n 3.57 3.50 N 5.93 10.22

13 s oer; 265-267 c 5 .90 55.20 n ;.s1 3.1 4 N 10.0: 10.10 14 9 P)302-303 c 5*..53 51.3. n 3.05 3.27 n 13.0? 17.91

EXAMPLE dicarboxylate (10 g.) and ammonia g.) in methanol Dimethyl2-(4-Pyridyl)imidazole-4,5-dicarboxylate Hydrochloric acid was bubbledinto a suspension of 2-(4-pyridyl)imidazole-4,5-dicarboxylic acid (30g.) in methanol (2.2 1.) at reflux for one hour. After an additionalhour of reflux the reaction mixture was concentrated to a solid.dissolved in water (500 ml.) and the resulting diester precipitated bythe addition of aqueous sodium bicarbonate solution. Afterrecrystallization from water 27 g. of dimethyl 2-(4-pyridyl)imidazole-4,5dicarboxylate was obtained which decomposed at196C.

Analysis for z u 3 4 Calc.: C. 55.17; H, 4.24; N. 16.09; Found: C,55.10; H. 4.44; N. 16.39.

In a similar manner dimethyl 2-(3-pyridyl)imidazole- 4,5-dicarboxylatemay be obtained by substituting 2- (3-pyridyl)imidazole-4,5-dicarboxylicacid for 2-(4- pyridyl)imidazole-4,5-dicarboxylic acid in the foregoingmethod and otherwise following the procedure described therein. Thedimethyl 2-(3-pyridyl)imida2ole- 4,5-dicarboxylate product has a meltingpoint of 212- 214C. and gave the following analysis:

Calc.: C. 55.17; H, 4.24; N. 16.09; Found: C. 55.01; H, 4.23; N. 16.04.

EXAMPLE 1 1 2-(4-Pyridyl )imidazole 4,5-dicarboxamide A mixture ofdimethyl 2-(4-pyridyl)imidazole-4,5-

(200 ml.) was heated at 120C. for 18 hours. The re- 20 sulting solid wasfiltered and after recrystallization from a mixture ofN,N-dimethylformamide and water 6.2 g. of2-(4-pyridyl)imidazole-4,S-dicarboxamide was obtained which melted above300C.

Analysis for CWHQN5OZ:

Calc.: C, 51.94; H, 3.92; N, 30.29; Found: c, 51.93; H, 3.92; N, 30.37.

EXAMPLE 12 Analysis for C H N Calc.: C, 61.53; H, 2.58; N, 35.88; Found:C, 61.06; H, 2.77; N, 35.53.

Examples 10-12 describe methods by which the 4,5- dicarboxy groups inthe 2-(4-pyridyl)imidazole-4,5-

dicarboxylic acid of Example 1 can be converted to the correspondingester, amide and cyano derivatives. Thus, Example 10 describes theconversion of the said dicarboxy derivative to its diesterifiedcounterpart and Examples 1 1-12 describe the conversion of the saiddiester to the corresponding amido and cyano derivatives. By followingthese procedures all of the instant products may be obtained. Thefollowing equation and Table ll illustrate the processes of Examples lOl2 and EXAMPLE 21 4(5 )-Carbomethoxy-2-(p-chlorophenyl )imidazole-5(4)-carboxylic Acid Sodium hydroxide (1,54 g., 0.038 mole) in water (40ml.) is added with stirring to a solution of dimethyl 2-(P-chlorophenyl)imidazole-4,5-dicarboxylate (l 1.3 g., 0.038 mole) in50% methanol (154 ml.). The reaction mixture was refluxed for 1.5 hours,cooled and acidithe products derived therefrom. The starting materials10 fied to congo red with hydrochloric acid. 4(5)- in these synthesesare the products of Examples l0-l 2.

R on f m llOt/c \T R 4 POCl P001 5 M140?! mr oui NC '2' nmco 6 i l 1 RNC Example R 4 Carbomethoxy-2-(p-chlorophenyl )-imidazole-5 4) AH 18 -Cll was concentrated under pressure to afford a residue which wasdissolved in water and the excess acid was neutralized with ammoniumhydroxide. On cooling a solid crystalized and this material was filteredto afford a crude product (4.8 g.) which was chromatographed on silicagel to afford 4(5)-cyano-2-(4-pyridyl)-5(4)- imidazolecarboxamide. Afterrecrystallization from a mixture of acetonitrile and water there wasobtained 550 mg. of 4(5)-cyano-2-(4-pyridyl)-5(4)- imidazolecarboxamidewhich melted above 300C.

Analysis for C H N O:

Calc.: C, 56.33; H. 3.31; N. 32.85; Found: C, 56.19; H, 3.27; N, 32.86.

EXAMPLE 23 EXAMPLE 24 2-(p-Chlorophenyl)-[4(5)-N-ethylcarbamoyl]imidazole-5(4)-carboxylic Acid By substituting ethylaminefor the methylamine of Example 24 and following the procedure describedtherein, the product 2-(p-chlorophenyl)-[4(5)-N-ethylcarbamoyH-S(4)-carboxylic acid is obtained.

EXAMPLE 25 2-(p-Chlor0phenyl)-[4(5)-N- allycarbamoyl]imidazole-5(4)-carboxylic Acid By substituting allylamine for the methylamine ofExample 24 and following the procedure described therein, there is thusobtained 2-(p-chlorophenyl)- [4(5 )-N-allylcarbamoyl]imidazole-5(4)-carboxylic acid.

EXAMPLE 26 2-(p-Chlorophenyl)-[4(5)-N-cyclopropylcarbamoyl]imidazole-5(4)-carboxylic Acid By substitutingcyclopropylamine for the methylamine of Example 24 and following theprocedure described therein, there is thus chlorophenyl)-[4( 5 )-N-cyclopropylcarbamoyl]imidazole-5(4)-carboxylic acid.

obtained 2-(p- I i The-pr'o ducts (ll'of the invention can be administered in a' wide: variety of therapeutic dosages .in conventionalvehicles as, for example, by oral administration in the form of acapsule or tableta's well as b'y'intra'venous injection. Also, thedosage'of the products may be varied over a wide range as, for example,in the form of capsulesor, scored tablets containing 5,10, 20,

25, 50, 1,00, 150, 2 50 and 500" milligrams, iie., from 5 to about 500milligrams, of the activeingredient for the symptomatic 'adjustmentofthe dosage to the patient to be treated. These dosages are well belowthe toxic or lethal dose of the products.

A suitable unit dosage form of the products of this invention can beprepared by mixing 50 mg. of an imidazole product (I) of this inventionor a suitable acid addition salt, or quaternary ammonium saltthereoflwith 144 mg. of lactose and 6 mg. of magnesium stearate andplacing the 200 mg. mixture into aNo. 3 gelatin capsule. Similarly, byemploying more of the active ingredient and less lactose, other dosageforms can be put up in No. 3 gelatin capsules and, should it benecessary to mix more than 200 mg. of ingredients together, largercapsules may be employed. Compressed tablets, pills or other desiredunit dosages can be prepared to incorporate the compounds of thisinvention by conventional methods and, if desired, can be made up aselixirs or as injectable solutions by methods well known to pharmacists.

It is also within the scope of this invention to combine two or more ofthe compounds of this invention in a unit dosage form or to combine oneor more of the compounds with other known diuretics and saluretics orwithv other desired therapeutic and/or nutritive agents in'dosage unitform.

The following exampleis included to illustrate the preparation of arepresentative dosage form:

EXAMPLE 27 Dry-filled capsules containing 50 mg. of active ingredientper capsule The 4,5-dicyano-2-"(4-pyridyl)imidazole is reduced to a No.60 powder and then lactose and magnesium stearate arepassed through aNo. 60 bolting cloth onto the powderand the combined ingredients admixedfor 10 minutes and then filled into No. 3 dry gelatin capsules.

Similar dry-filled capsules can be prepared by replacing the activeingredientof the above example by any of the other novel compounds ofthis invention.

It will be apparent from the foregoing description that the imidazoleproducts of this invention constitute a valuable class of compoundswhich have not been prepared heretofore. One skilled in the art willalso appreciate that the processes disclosed in the above examples aremerely illustrative and are capable of a wide variation and modificationwithout departing from the spirit of this invention.

What is claimed is: l. A compound of the formula:

wherein R is naphthyl, or an aryl radical of the formula:

wherein X is halo, lower alkoxy or lower alkanamido and R and R are thesame or different and represent carboxy, lower alkoxycarbonyl, and thenon-toxic,

ical of the formula:

wherein X is halo, lower alkoxy or lower alkanamido.

4. The compound of claim 1 wherein R is phenyl carring a loweralkanamido substituent.

5. 2-(4-acetamidophenyl)imidazole-4,5-dicarboxylic acid.

1. A COMPOUND OF THE FORMULA:
 2. A compound of claim 1 wherein both R1and R2 moieties are carboxy.
 3. The compound of claim 1 wherein R is anaryl radical of the formula:
 4. The compound of claim 1 wherein R isphenyl carring a lower alkanamido substituent. 5.2-(4-acetamidophenyl)imidazole-4,5-dicarboxylic acid.